Project Summary/Abstract Many new pharmacological treatments for Down syndrome (DS), the most frequent genetic cause of intellectual disability (ID), are on their way to clinical trial. It is therefore important that there be appropriate and well-validated cognitive measures to assess their efficacy. We should expect these measures to be supported by current neuroscientific understanding of the cognitive tasks they are designed to assess. This is the aim of the current proposal: to support the validity of memory measures for use with children with ID. Many new and developing pharmaceuticals are designed to work on the hippocampus and associated medial temporal lobe memory systems, but little work has been done developing tests for ID populations that specifically and comprehensively asses the memory systems known to correspond with these structures. For this reason, the parent study has developed and is validating a comprehensive screen-based memory assessment and other standard memory outcomes (the NIH toolbox) for children with ID. The current proposal sets a goal of assessing a subset of the parent grant participants (n=30 DS, n=30 typically developing children (TD), ages 11-17 years), with magnetic resonance imaging (MRI). MRI visits will take place at the University of Arizona where we will collect structural data and functional resting state scans for these participants, with a focus on hippocampal integrity. The imaging data will make use of protocols developed by co-Is and mentors Chou and Chen that are designed specifically for difficult-to-scan populations. The training candidate will also benefit from the developmental cognitive neuroscience and DS expertise from parent award investigators Edgin (PI) and Lee (co-I). Imaging data will be analyzed for correlation with memory measures in support of the aims of the parent study, specifically to provide scientific support for 1) alternate form equivalence, 2) evaluation of measurement reliability and validity, 3) evaluation of a syndrome-specific memory profile of DS, in the context of 4) measurement of problem behavior. We will also analyze these imaging data alongside sleep data gathered for the same participants through a competitive supplement, as sleep disruption may influence both medial temporal lobe functioning and cognitive abilities. This project will provide brain-based evidence regarding the correlates of these neuropsychological measures, a critical research gap required to demonstrate their validity. These data will allow us to deepen our support for determining which measures may provide strong primary outcomes for clinical trials in DS. The results of the proposed project will be novel in terms of both neuroimaging data collection and in terms of the richness of memory data collected for the same participants, which will allow us to more specifically understand the DS memory profile and provide well- researched support for the memory measures assessed under the parent grant.